Nectin and Nectin-like (Nec-1) molecules are cell surface molecules that mediate cell-cell adhesion and are strongly expressed on tumor cells. NK cells and T cells express receptors that bind Nectins and Nectin-like (Necl) molecules. The importance of Nectin and Necl recognition in anti-tumor immune responses in vivo is unclear though in vitro these receptors allow lymphocytes to recognize and kill tumor cells. In this grant proposal, we will examine importance of the interaction between Necl-2, a nectin-like molecule, and its ligand class I-restricted T cell-associated molecule (CRTAM). In our preliminary studies, we have discovered that NK cells and CDS T cells recognize Necl-2, through a receptor known as (CRTAM). This interaction promotes target cell killing and IFN-y secretion in NK cells and CDS T cells in vitro. Furthermore, Necl-2 has been previously shown to suppress tumorigenesis in vivo and its expression is silenced in many epithelial tumors. We hypothesize that the CRTAM/Necl-2 interaction is a novel and important immunosurveillance strategy in vivo. Tumors may suppress Necl-2 expression to evade this immunosurveillance mechanism. In Specific Aim 1, we will evaluate the impact of CRTAM/Necl-2 interaction in short-term and long-term rejection of primary and metastatic tumors expressing Necl-2 in vivo. In Specific Aim 2 we will determine the impact of CRTAM/Necl-2 interaction on proliferation, cytokine secretion and anergy of anti-tumor CDS T cells using a model in which the tumor cells express a well-defined tumor-associated antigen. Moreover, we will assess if CRTAM/Necl-2 interaction enhances CDS T cell responses to tumor vaccines that either express or do not express a defined tumor-associated antigen. Our discovery and initial characterization of the CRTAM/Necl-2 interaction and its potential role in immunosurveillance places our laboratory in a unique position to examine this interaction in detail. We have extensive expertise in NK biology and priming of T cell responses, and we are in a privileged position to investigate whether recognition of Necl-2 by CRTAM allows the immunosurveillance network to distinguish tumor cells from normal cells in vivo. [unreadable] [unreadable]